Vitronectin receptor antagonist

Abstract

Compounds of the formula (I): are vitronectin receptor antagonists useful in the treatment of osteoporosis.

What is claimed is:  
     
       1. A compound according to formula (1):                    
       wherein: 
       R 1  is R 7 , or A-C 0-4 alkyl, A-C 2-4 alkenyl, A-C 2-4 alkynyl, A-C 3-4 oxoalkenyl, A-C 3-4 oxoalkynyl, A-C 1-4 aminoalkyl, A-C 3-4 aminoalkenyl, A-C 3-4 aminoalkynyl, optionally substituted by any accessible combination of one or more of R 10  or R 7 ;  
       X is O, C(O)NR′, or NR′C(O);  
       A is H, C 3-6 cycloalkyl, Het or Ar;  
       R 7  is —COR 8 , —COCR′ 2 R 9 , —C(S)R 8 , —S(O) m OR′, —S(O) m NR′R″, —PO(OR′), —PO(OR) 2 , —B(OR) 2 , —NO 2 , or tetrazolyl;  
       each R 8  independently is —OR′, —NRR″, —NR′SO 2 R′, —NR′OR′, or —OCR′ 2 CO(O)R′;  
       R 9  is —OR′, —CN, —S(O) r R′, —S(O) m NR′ 2 , —C(O)R′, C(O)NR′ 2 , or —CO 2 R′;  
       R 10  is H, halo, —OR 11 , —CN, —NR′R 11 , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R′, —CONR′ 2 , A-C 0-6 alkyl-, A-C 1-6 oxoalkyl-, A-C 2-6 alkenyl-, A-C 2-6 alkynyl-, A-C 0-6 alkyloxy-, A-C 0-6 alkylamino- or A-C 0-6 alkyl-S(O) r -;  
       R 11  is R′, —C(O)R′, —C(O)NR′ 2 , —C(O)OR′, —S(O) m R′, or —S(O) m NR′ 2 ;  
       R 2  is                    
       W is —(CHR g ) a —U—(CHR g ) b —;  
       U is absent or CO, CR g   2 , C(═CR g   2 ), S(O) k , O, NR g , CR g OR g , CR g (OR k )CR g   2 , CR g   2 CR g (OR k ), C(O)CR g   2 , CR g   2 C(O), C(O)NR i , NR i C(O), OC(O), C(O)O, C(S)O, OC(S), C(S)NR g , NR g C(S), S(O) 2 NR g , NR g S(O) 2  N═N, NR g NR g , NR g CR g   2 , NR g CR g   2 , CR g   2 O, OCR g   2 , C≡C or CR g ═CR g ;  
       G is NR e , S or O,  
       R g  is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl or Ar-C 0-6 alkyl;  
       R k  is R g , —C(O)R g , or —C(O)OR f ;  
       R i  is is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl, or C 1-6 alkyl substituted by one to three groups chosen from halogen, CN, NR g   2 , OR g , SR g , CO 2 R g , and CON(R g ) 2 ;  
       R f  is H, C 1-6 alkyl or Ar-C 1-6 alkyl;  
       R e  is H, C 1-6 alkyl, Ar-C 1-6 alkyl, Het-C 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl, or (CH 2 ) k CO 2 R g ;  
       R b  and R c  are independently selected from H, C 1-6 alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 , or R b  and R c  are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF 3 , C 1-4 alkyl, OR f , S(O) k R f , COR f , CO 2 R f , OH, NO 2 , N(R f ) 2 , CO(NR f ) 2 , and CH 2 N(R f ) 2 ; or methylenedioxy;  
       Q 1 , Q 2 , Q 3  and Q 4  are independently N or C—R y , provided that no more than one of Q 1 , Q 2 , Q 3  and Q 4  is N;  
       R′ is H, C 1-6 alkyl, Ar-C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl;  
       R″ is R′, —C(O)R′ or —C(O)OR′;  
       R′″ is H, C 1-6 alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 ;  
       R y  is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R g , —COR g  or —CONR g   2 , or C 1-6 alkyl optionally substituted by halo, —OR g , —SR g , —CN, —NR g R″, —NO 2 , —CF 3 , R′S(O) r —, —CO 2 R g , —COR g  or —CONR 9   2 ;  
       a is 0, 1 or 2;  
       b is 0, 1 or 2;  
       k is 0, 1 or 2;  
       m is 1 or 2;  
       r is 0, 1 or 2;  
       s is 0, 1 or 2;  
       u is 0 or 1;and  
       v is 0 or 1;  
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. A compound according to claim  1  in which X is O. 
     
     
       3. A compound according to claim  2  in which R 2  is                    
       wherein Q 1 , Q 2 , and Q 3  are each CR y , Q 4  is CR y  or N and u is 0. 
     
     
       4. A compound according to claim  3  in which each R′ is H, R″ is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, C(O)OC 1-6 alkyl, —C(O)C 0-6 alkyl-Ar, or C(O)OC 0-6 alkyl-Ar, W is —CH 2 —CH 2 —, and R y  is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R g , —COR g —CONR g   2 , or C 1-6 alkyl. 
     
     
       5. A compound according to claim  1  in which R 2  is                    
       wherein Q 1 , Q 2 , and Q 3  are each CH and u is 0. 
     
     
       6. A compound according to claim  5  in which each R′ is H, R″ is H or C 1-4 alkyl and W is —CH 2 —CH 2 —. 
     
     
       7. A compound according to claim  1  which is (±)-2-(2-pyridylamino)propoxy-6,7,8,9-tetrahydro-7-oxo-5H-benzocycloheptenyl-6-acetic acid or a pharmaceutically acceptable salt thereof. 
     
     
       8. A pharmaceutical composition which comprises a compound according to claim  1  and a pharmaceutically acceptable carrier. 
     
     
       9. A method of treating a disease state in which antagonism of the vitronectin receptor is indicated which comprises administering a compound according to claim  1 . 
     
     
       10. A method of inhibiting angiogenesis which comprises administering a compound according to claim  1 . 
     
     
       11. A method of treating atherosclerosis, restenosis, inflammation, cancer or osteoporosis which comprises administering a compound according to claim  1 . 
     
     
       12. A compound according to formula (II):                    
       wherein: 
       R 1  is R 7 , or A-C 0-4 alkyl, A-C 2-4 alkenyl, A-C 2-4 alkynyl, A-C 3-4 oxoalkenyl, A-C 3-4 oxoalkynyl, A-C 1-4 aminoalkyl, A-C 3-4 aminoalkenyl, A-C 3-4 aminoalkynyl, optionally substituted by any accessible combination of one or more of R 10  or R 7 ;  
       X is O, C(O)NR′, or NR′C(O);  
       A is H, C 3-6 cycloalkyl, Het or Ar;  
       R 7  is —COR 8 , —COCR′ 2 R 9 , —C(S)R 8 , —S(O) m OR′, —S(O) m NR′R″, —PO(OR′), —PO(OR′) 2 , —B(OR′) 2 , —NO 2 , or tetrazolyl;  
       each R 8  independently is —OR′, —NR′R″, —NR′SO 2 R′, —NR′OR′, or —OCR′ 2 CO(O)R′;  
       R 9  is —OR′, —CN, —S(O) r R′, —S(O) m NR′ 2 , —C(O)R′, C(O)NR′ 2 , or —CO 2 R′;  
       R 10  is H, halo, —OR 11 , —CN, —NR′R 11 , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R′, —CONR′ 2 , A-C 0-6 alkyl-, A-C 1-6 oxoalkyl-, A-C 2-6 alkenyl-, A-C 2-6 alkynyl-, A-C 0-6 alkyloxy-, A-C 0-6 alkylamino- or A-C 0-6 alkyl-S(O) r -;  
       R 11  is R′, —C(O)R′, —C(O)NR′ 2 , —C(O)OR′, —S(O) m R′, or —S(O) m NR′ 2 ;  
       R 2  is                    
       W is —(CHR g ) a —U—(CHR g ) b —;  
       U is absent or CO, CR g   2 , C(═CR g   2 ), S(O) k , O, NR g , CR g OR g , CR g (OR k )CR g   2 , CR g   2 CR g (OR k ), C(O)CR g   2 , CR g   2 C(O), CON R i  N R i  CO OC(O), C(O)O, C(S)O, OC(S), C(S)NR 9 , NR g C(S), S(O) 2 NR g , NR g S(O) 2  N═N, NR g NR g , NR g CR g   2 , NR gCR   g   2 , CR g   2 O, OCR g   2 , C≡C or CR g ═CR g ;  
       G is NR e , S or O;  
       R g  is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl or Ar-C 0-6 alkyl;  
       R k  is R 8 , —C(O)R g , or —C(O)OR f ;  
       R i  is is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl, or C 1-6 alkyl substituted by one to three groups chosen from halogen, CN, NR g   2 , OR g , SR g , CO 2 R g , and CON(R g ) 2 ;  
       R f  is H, C 1-6 alkyl or Ar-C 1-6 alkyl;  
       R e  is H, C 1-6 aikyl, Ar-C 1-6 alkyl, Het-C 1-6 alkyl, C 3-7 cycloalkyl-C 1-6 alkyl, or (CH 2 ) k CO 2 R g ;  
       R b  and R c  are independently selected from H, C 1-6 alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 , or R b  and R c  are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF 3 , C 1-4 alkyl, OR f , S(O) k R f , COR f , CO 2 R f , OH, NO 2 , N(R f ) 2 , CO(NR f ) 2 , and CH 2 N(R f ) 2 ; or methylenedioxy;  
       Q 1 , Q 2 , Q 3  and Q 4  are independently N or C—R y , provided that no more than one of Q 1 , Q 2 , Q 3  and Q 4  is N;  
       R′ is H, C 1-6 alkyl, Ar-C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl;  
       R″ is R′, —C(O)R′ or —C(O)OR′;  
       R′″ is H, C 1-6 alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl, or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(R f ) 2 , CO(NR f ) 2 , CH 2 N(R f ) 2 ;  
       R y  is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R g , —COR G  or —CONR g   2 , or C 1-6 alkyl optionally substituted by halo, —OR g , —SR g , —CN, —NR g R″, —NO 2 , —CF 3 , R′S(O) r —, —CO 2 R g , —COR g  or —CONR g   2 ;  
       a is 0, 1 or 2;  
       b is 0, 1 or 2;  
       k is 0, 1 or 2;  
       m is 1 or 2;  
       r is 0, 1 or 2;  
       s is 0, 1 or 2;  
       u is 0 or 1; and  
       v is 0 or 1;  
       or a pharmaceutically acceptable salt thereof. 
     
     
       13. A compound according to claim  11  which is methyl (±)-2-(2-pyridylamino)propoxy-6,7,8,9-tetrahydro-7-oxo-5H-benzocycloheptenyl-6-acetate or a pharmaceutically acceptable salt thereof. 
     
     
       14. A compound according to formula (III):                    
       R 1  is R 7 , or A-C 0-4 alkyl, A-C 2-4 alkenyl, A-C 2-4 alkynyl, A-C 3-4 oxoalkenyl, A-C 3-4 oxoalkynyl, A-C 1-4 aminoalkyl, A-C 3-4 aminoalkenyl, A-C 3-4 aminoalkynyl, optionally substituted by any accessible combination of one or more of R 10  or R 7 ;  
       X is O, C(O)NR′, or NR′C(O);  
       A is H, C 3-6 cycloalkyl, Het or Ar;  
       R 7  is —COR 8 , —COCR′ 2 R 9 , —C(S)R 8 , —S(O) m OR′, —S(O) m NR′R″, —PO(OR′), —PO(OR′) 2 , —B(OR′) 2 , —NO 2 , or tetrazolyl;  
       each R 8  independently is —OR′, —NR′R″, —NR′SO 2 R′, —NR′OR′, or —OCR′ 2 CO(O)R′;  
       R 9  is —OR′, —CN, —S(O) r R′, —S(O) m NR′ 2 , —C(O)R′, C(O)NR′ 2 , or —CO 2 R′;  
       R 10  is H, halo, —OR 11 , —CN, —NR′R 11 , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R′, —CONR′ 2 , A-C 0-6 alkyl-, A-C 1-6 oxoalkyl-, A-C 2-6 alkenyl-, A-C 2-6 alkynyl-, A-C 0-6 alkyloxy-, A-C 0-6 alkylamino or A-C 0-6 alkyl-S(O) r -;  
       R 11  is R′, —C(O)R′, —C(O)NR′ 2 , —C(O)OR′, —S(O) m R′ or —S(O) m NR′ 2 ;  
       W is —(CHR g ) a —U—(CHR g ) b —;  
       U is absent or CO, CR g   2 , C(═CR g   2 ), S(O) k , O, NR g , CR g OR g , CR g (OR k )CR g   2 , CR g   2 CR g (OR k ), C(O)CR g   2 , CR g   2 C(O), CON R i  N R i  CO OC(O),  
       C(O)O, C(S)O, OC(S), C(S)NR g , NR g C(S), S(O) 2 NR g , NR g S(O) 2  N═N, NR g NR g , NR g CR g   2 , NR g CR g   2 , CR g   2 O, OCR g   2 , C≡C or CR g ═CR g ;  
       R g  is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl or Ar-C 0-6 alkyl;  
       R k  is R g , —C(O)R g , or —C(O)OR f ;  
       R i  is is H, C 1-6 alkyl, Het-C 0-6 alkyl, C 3-7 cycloalkyl-C 0-6 alkyl, Ar-C 0-6 alkyl, or C 1-6 alkyl substituted by one to three groups chosen from halogen, CN, NR g   2 , OR g , SR g , CO 2 R g , and CON(R g ) 2 ;  
       R f  is H, C 1-6 alkyl or Ar-C 1-6 alkyl;  
       Q 1 , Q 2 , Q 3  and Q 4  are independently N or C-RY, provided that no more than one of Q 1 , Q 2 , Q 3  and Q 4  is N;  
       R′ is H, C 1-6 alkyl, Ar-C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl;  
       R″ is R′, —C(O)R′ or —C(O)OR′;  
       R y  is H, halo, —OR g , —SR g , —CN, —NR g R k , —NO 2 , —CF 3 , CF 3 S(O) r —, —CO 2 R g , —COR g  or —CONR g   2 , or C 1-6 alkyl optionally substituted by halo, —OR g , —SR g , —CN, —NR g R″, —NO 2 , —CF 3 , R′S(O) r —, -CO 2 R g , —COR g  or —CONR g   2 ;  
       a is 0, 1 or 2;  
       b is 0, 1 or 2;  
       m is 1 or 2; and  
       r is 0, 1 or 2;  
       or a pharmaceutically acceptable salt thereof.